Vancomycin Dosing Regimens Research Articles

Vancomycin Dosing in Patients on Intermittent Hemodialysis-A Retrospective Study.

To determine the incidence of therapeutic target attainment using a three-times per week protocol for vancomycin therapy given during the last hour of intermittent hemodialysis (HD). A single-center retrospective cohort study was conducted of patient medical records in a remote dialysis center from January 2017 to July 2023. Adult patients with chronic kidney disease stage 5 on ≥3 months of intermittent HD who had received a course of vancomycin therapy with ≥1 serum vancomycin concentration recorded were included. Demographic and dosing data were collected. Clinician adherence with the dosing protocol and attainment of the therapeutic target (trough concentration within 15-20 mg/L) following the loading and maintenance doses were assessed. Factors associated with target nonattainment following the loading dose were analyzed, and the 48- and 72-h maintenance dosing intervals were analyzed for target nonattainment. A total of 98 vancomycin courses (67 patients) were available for analysis. Only 38% of the loading doses were prescribed as per protocol. Following the loading dose, 25% of trough concentrations achieved the therapeutic target concentration (15-20 mg/L), 25% returned a supra-therapeutic concentration (>20 mg/L) and 50% were sub-therapeutic (<15 mg/L). When compared with those achieving target, sub-therapeutic concentrations were associated with a lower loading dose (median 16.6 vs 20.0 mg/kg, P < 0.002), and supra-therapeutic concentrations had a shorter dosing interval between the loading dose and first maintenance dose (median 31.5 vs 39.0 h, P = 0.06). Of the 201 maintenance trough concentrations collected, 65% were therapeutic, 21% were sub-therapeutic and 14% were supra-therapeutic, with an overall median trough concentration of 17.3 mg/L. As the treatment duration increased, an increase was seen in the number of dose adjustments required to achieve the target trough concentration. The 48-h dosing interval was associated with more supra-therapeutic concentrations and the 72-h interval was associated with more sub-therapeutic concentrations (df = 2, P = 0.022). We have identified a high rate of target nonattainment for HD patients on a three times a week vancomycin dosing regimen. We recommend a loading dose of 20 to 25 mg/kg irrespective of the indication and a better-defined dosing interval after the loading dose. A higher maintenance dose should be prescribed when the time to next dialysis session is 72 h. Further pharmacokinetic studies are needed to assess factors influencing target concentration attainment following the maintenance doses and to determine an optimal dosing regimen.

Dose Optimization of Vancomycin in Pediatric Post-Cardiac Surgery Patients: A Population Pharmacokinetic Modeling Study.

Vancomycin is a glycopeptide antibiotic used for the treatment of severe gram-positive infections. Despite decades of clinical experience, optimized dosing for vancomycin in pediatric populations still warrants further investigation. Patients admitted to the pediatric intensive care unit (PICU) after cardiac surgery are often treated with vancomycin in case of (suspected) infection. However, vancomycin dosing in this population is often challenging due to fluctuations in volume status, (temporarily) compromised renal function or the use of diuretics or extracorporeal membrane oxygenation (ECMO). The main objective of this study was to describe vancomycin pharmacokinetics (PK) in pediatric cardiac surgery patients. Secondary objectives were to potentially optimize vancomycin dosing and to assess the suitability of the model to be used for model informed precision dosing (MIPD). A retrospective cohort study was performed with patients admitted to the PICU of the Leiden University Medical Center. Clinical data from post-cardiac surgery PICU patients receiving intravenous vancomycin between January 2020 and December 2023 were included in the analysis. Patients received vancomycin 10 mg/kg 4 times daily (qid), after which a trough concentration was generally sampled just before the fourth dose. Pharmacokinetic data were used to develop a population PK model by using a non-linear mixed effects modeling approach (NONMEM). In addition, potential covariates such as renal function, body weight (BW) and post-menstrual age were tested. The final model was used for vancomycin dose optimization using Monte Carlo simulations. In total, 193 pediatric post-cardiac surgery patients, contributing a total of 706 vancomycin blood samples were included. The 2-compartmental population PK model best described the data. Renal function and BW were identified as significant and clinically relevant covariates on vancomycin PK. Model parameters were: elimination clearance: 4.01 L/min at 70 kg; intercompartmental clearance: 0.425 L/min at 70 kg; central volume of distribution: 56.1 L/70 kg; and peripheral volume of distribution: 21.7 L/70 kg (fixed). Dose simulations suggested a non-linear dosing algorithm, with relatively lower per kg dose for increasing BW to be optimal for our population. Furthermore, the model was considered to be suitable for the (a posteriori) prediction of future vancomycin serum concentrations. We successfully developed a population PK model for vancomycin in post-cardiac surgery children. Vancomycin PK were shown to be significantly influenced by serum creatinine and BW. Furthermore, we suggest a new vancomycin dosing regimen based on allometric scaling. The developed PK model can be used for model informed precision dosing of vancomycin in pediatric post-cardiac surgery patients.

Evaluation of Vancomycin Dose Needed to Achieve 24-Hour Area Under the Concentration-Time Curve to Minimum Inhibitory Concentration Ratio Greater Than or Equal to 400 Using Pharmacometric Approaches in Pediatric Intensive Care Patients.

To investigate which independent factor(s) have an impact on the pharmacokinetics of vancomycin in critically ill children, develop an equation to predict the 24-hour area under the concentration-time curve from a trough concentration, and evaluate dosing regimens likely to achieve a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) greater than or equal to 400. Prospective population pharmacokinetic study of vancomycin. Critically ill patients in quaternary care PICUs. Children 90 days old or older to younger than 18 years who received IV vancomycin treatment, irrespective of the indication for use, in the ICUs at the University of Maryland Children's Hospital and Texas Children's Hospital were enrolled. Vancomycin was prescribed at doses and intervals chosen by the treating clinicians. A median of four serum levels of vancomycin per patient were collected along with other variables for up to 7 days following the first administration. These data were used to characterize vancomycin pharmacokinetics and evaluate the factors affecting the variability in achieving AUC24/MIC ratio greater than or equal to 400 in PICU patients who are not on extracorporeal therapy. A total of 302 children with a median age of 6.0 years were enrolled. A two-compartment model described the pharmacokinetics of vancomycin with the clearance of 2.76 L/hr for a typical patient weighing 20 kg. The glomerular filtration rate estimated using either the bedside Schwartz equation or the chronic kidney disease in children equation was the only statistically significant predictor of clearance among the variables evaluated, exhibiting equal predictive performance. The trough levels achieving AUC24/MIC = 400 were 5.6-10.0 μg/mL when MIC = 1 μg/mL. The target of AUC24/MIC greater than or equal to 400 was achieved in 60.4% and 36.5% with the typical dosing regimens of 15 mg/kg every 6 and 8 hours (q6h and q8h), respectively. The pharmacokinetics of vancomycin in critically ill children were dependent on the estimated glomerular filtration rate only. Trough concentrations accurately predict AUC24. Typical pediatric vancomycin dosing regimens of 15 mg/kg q6h and q8h will often lead to AUC24/MIC under 400.

Optimal Weight-Based Dosing of Vancomycin to Achieve an Area Under the Curve of 400 to 600 Stratified by Body Mass Index

Background: In 2020, the American Society of Health System Pharmacist (ASHP) and Infectious Diseases Society of America (IDSA) published a consensus guideline for vancomycin management, recommending area under the curve (AUC) as the preferred monitoring strategy. These guidelines recommend doses of 15-20 mg/kg every 8 to 12 hours for most patients with normal renal function. However, in extreme body weights, standard dosing may deviate to provide a therapeutic AUC. The primary objective of this pharmacokinetic study is to evaluate the optimal vancomycin weight-based dosing strategy that achieves a therapeutic AUC of 400-600 stratified by body mass index (BMI). The secondary objective is to evaluate the incidence of acute kidney injury (AKI) based on BMI. Methods: Patients were identified from two sites within the Department of Veterans Affairs who received vancomycin for at least 48 hours and had at least one steady-state level from January 2015 through July 2022. Regimens with a frequency of ≤8 hours or patients with baseline creatine clearance of &lt; 5 0 ml/min were excluded. Patients were categorized based on the Center for Disease Control BMI groups: healthy weight, overweight, or obese. The online vancomycin calculator, VancoPK©, was utilized to calculate AUC. Renal function at baseline and during vancomycin therapy was collected. Descriptive statistics were used for data analysis. Continuous outcomes were summarized using mean and standard deviation. The primary and secondary endpoints were analyzed using the analysis of variance and Fisher’s exact tests, respectively. Statistical significance was established at a p-value of &lt; 0 .05. Results: A total of 347 unique vancomycin regimens were included: 120 in the healthy weight group, 101 in the overweight group, and 126 in the obese group. The average total daily doses that achieved a therapeutic AUC were 1971mg (15.6mg/kg/dose), 2298mg (15mg/kg/dose), and 2524mg (12.6mg/kg/dose) for the healthy weight, overweight, and obese groups, respectively. There was a statistically significant difference among these groups. AKI occurred in 10/254 (3.9%) unique patients: 2/89 (2.2%) in the healthy weight group, 3/71 (4.2%) in the overweight group, and 5/94 (5.3%) in the obese group. This did not reach statistical significance. Conclusions: Vancomycin dosing regimens largely followed guideline recommendations. However, the average vancomycin mg/kg/dose that achieved a therapeutic AUC decreased as BMI increased, which was a statistically significant trend. While further research is needed to draw clinically impactful conclusions, these findings suggest that a lower mg/kg vancomycin dose in obesity may be needed to achieve therapeutic targets.

Vancomycin: An analysis and evaluation of eight population pharmacokinetic models for clinical application in general adult population.

Based on the recent guidelines for vancomycin therapeutic drug monitoring (TDM), the area under the curve to minimum inhibitory concentration ratio was to be employed combined with the usage of population pharmacokinetic (popPK) model for dosing adaptation. Yet, deploying these models in a clinical setting requires an external evaluation of their performance. This study aimed to evaluate existing vancomycin popPK models from the literature for the use in TDM within the general patient population in a clinical setting. The models under external evaluation were chosen based on a review of literature covering vancomycin popPK models developed in general adult populations. Patients' data were collected from Charles-Le Moyne Hospital (CLMH). The external evaluation was performed with NONMEM® (v7.5). Additional analyses such as evaluating the impact of number of samples on external evaluation, Bayesian forecasting, and a priori dosing regimen simulations were performed on the best performing model. Eight popPK models were evaluated with an independent dataset that included 40 patients and 252 samples. The model developed by Goti and colleagues demonstrated superior performance in diagnostic plots and population predictive performance, with bias and inaccuracy values of 0.251% and 22.7%, respectively, and for individual predictive performance, bias and inaccuracy were -4.90% and 12.1%, respectively. When limiting the independent dataset to one or two samples per patient, the Goti model exhibited inadequate predictive performance for inaccuracy, with values exceeding 30%. Moreover, the Goti model is suitable for Bayesian forecasting with at least two samples as prior for the prediction of the next trough concentration. Furthermore, the vancomycin dosing regimen that would maximize therapeutic targets of area under the curve to minimum inhibitory concentration ratio (AUC24/MIC) and trough concentrations (Ctrough) for the Goti model was 20 mg/kg/dose twice daily. Considering the superior predictive performance and potential for Bayesian forecasting in the Goti model, future research aims to test its applicability in clinical settings at CLMH, both in a priori and a posteriori scenario.

Impact Of Pharmacist Led Therapeutic Drug Monitoring of Vancomycin in Pediatric Cancer Patients

Aim This study aimed to evaluate the dosing regimen and therapeutic drug monitoring of vancomycin in this patient population. Method The study included 100 pediatric patients (3 months to 15 years) with various gram-positive bacterial infections. All patients received the initial vancomycin dose of 15 mg/kg every 6 hours. The researchers evaluated the incidence of achieving desired trough levels with this dosing regimen. Results The results revealed that patients between 1.0 and 5.9 years of age were less likely to achieve the desired trough levels with the initial vancomycin dose. Consequently, dose adjustments were made for patients with sub-therapeutic trough levels. These adjustments involved a 25% increase in the vancomycin dose. Importantly, the study found that the higher vancomycin dosing did not have any harmful effects on kidney function in pediatric patients, and no significant adverse effects were observed. Conclusion The dosing regimen of 15 mg/kg every 6 hours was unlikely to achieve the desired trough concentrations in pediatric patients with complicated infections and oncological diseases. The study recommends dose adjustments for the treatment of different infections in this population to increase the likelihood of reaching therapeutic steady-state concentrations of vancomycin.

Cost-effectiveness analysis of several dosage regimens of vancomycin in ventilator-associated pneumonia critically ill patients

This study aimed to identify the most cost-effective vancomycin dosage regimen to treat ventilator-associated pneumonia (VAP) in critically ill patients infected with “minimum inhibitory concentration (MIC) Creep” Methicillin-resistant Staphylococcus aureus (MRSA). Decision tree analysis with a healthcare provider perspective was used in this study. Clinical data, both efficacy and safety, were derived from Monte Carlo Simulation (MCS). Only direct medical cost was calculated in this study without any discounting factor analysis. The most cost-effective dosage regimen is the dosage regimen with the lowest incremental cost-effectiveness ratio (ICER). MCS found that the standard dose of vancomycin (2 g/day) was ineffective in treating MRSA with MIC 2 mg/l. The dosage regimen with a total daily dose of 4 g afforded the highest efficacy for all MIC values of MRSA. Nevertheless, this dosage regimen also afforded the highest risk of nephrotoxicity. The dosage regimen with a total daily dose of 3 g vancomycin attained a relatively good efficacy and safety profile. The ICER for vancomycin 1 g every 8 hours, 1 g every 6 hours, 1.5 g every 12 hours, and 2 g every 12 hours were 50,464; 58,998; 49,809; and 57,153, respectively. Vancomycin 1.5 g every 12 hours was the most cost-effective dosage regimen to treat VAP patients without advanced renal impairment in the era of “MIC Creep” MRSA.

Impact of vancomycin therapeutic drug monitoring on mortality in sepsis patients across different age groups: a propensity score-matched retrospective cohort study.

Due to its potent antibacterial activity, vancomycin is widely used in the treatment of sepsis. Therapeutic drug monitoring (TDM) can optimize personalized vancomycin dosing regimens, enhancing therapeutic efficacy and minimizing nephrotoxic risk, thereby potentially improving patient outcomes. However, it remains uncertain whether TDM affects the mortality rate among sepsis patients or whether age plays a role in this outcome. We analyzed data from the Medical Information Mart of Intensive Care-IV database, focusing on sepsis patients who were admitted to the intensive care unit (ICU) and treated with vancomycin. The primary variable of interest was the use of vancomycin TDM during the ICU stay. The primary outcome was 30-day mortality. To control for potential confounding factors and evaluate associations, we used Cox proportional hazards regression and propensity score matching (PSM). Subgroup and sensitivity analyses were performed to assess the robustness of our findings. Furthermore, restricted cubic spline models were utilized to investigate the relationship between age and mortality among different groups of sepsis patients, to identify potential non-linear associations. A total of 14,053 sepsis patients met the study criteria, of whom 6,826 received at least one TDM during their ICU stay. After PSM, analysis of 4,329 matched pairs revealed a significantly lower 30-day mortality in the TDM group compared with the non-TDM group (23.3% vs.27.7%, p < 0.001). Multivariable Cox proportional hazards regression showed a significantly reduced 30-day mortality risk in the TDM group [adjusted hazard ratio (HR): 0.66; 95% confidence interval (CI): 0.61-0.71; p < 0.001]. This finding was supported by PSM-adjusted analysis (adjusted HR: 0.71; 95% CI: 0.66-0.77; p < 0.001) and inverse probability of treatment weighting analysis (adjusted HR: 0.72; 95% CI: 0.67-0.77; p < 0.001). Kaplan-Meier survival curves also indicated significantly higher 30-day survival in the TDM group (log-rank test, p < 0.0001). Subgroup analyses by gender, age, and race yielded consistent results. Patients with higher severity of illness-indicated by sequential organ failure assessment scores ≥6, acute physiology score III ≥40, or requiring renal replacement therapy, vasopressors, or mechanical ventilation-experienced more pronounced mortality improvement from vancomycin TDM compared with those with lower severity scores or not requiring these interventions. The results remained robust after excluding patients with ICU stays <48 h, those with methicillin-resistant Staphylococcus aureus infections, or when considering only patients with septic shock. In subgroup analyses, patients under 65 years (adjusted HR: 0.50; 95% CI: 0.43-0.58) benefited more from vancomycin TDM than those aged 65 years and older (adjusted HR: 0.75; 95% CI: 0.67-0.83). Notably, sepsis patients aged 18-50 years had the lowest mortality rate among all age groups, at 15.2% both before and after PSM. Furthermore, in this age group, vancomycin TDM was associated with a greater reduction in 30-day mortality risk, with adjusted HRs of 0.32 (95% CI: 0.24-0.41) before PSM and 0.30 (95% CI: 0.22-0.32) after PSM. Vancomycin TDM is associated with reduced 30-day mortality in sepsis patients, with the most significant benefit observed in patients aged 18-50. This age group exhibited the lowest mortality rates and experienced the greatest reduction in mortality following TDM compared with older patients.

Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

Reappraisal of therapeutic vancomycin trough concentrations with empirical dosing in neonatal infections.

Vancomycin is commonly used for neonatal sepsis. However, consensus on an empirical neonatal vancomycin regimen remains uncertain. We aimed to reappraise the therapeutic optimum concerning vancomycin trough concentrations with empirical dosing and to evaluate the relationship between trough concentrations and predicted 24-h area under the curve (AUC24). This was a 3-year retrospective study. Neonates who were admitted to the neonatal intensive care unit with available vancomycin trough concentrations were enrolled. Trough levels were obtained before the fourth dose. Achievement of goal trough after implementing the vancomycin dosing regimen was based on the Practical Neonatology Medical Manual, published by the National Taiwan University College of Medicine. A total of 46 neonates were included for analysis. Coagulase-negative staphylococci were the most commonly identified pathogens of sepsis. Among these patients, 22 achieved goal trough levels of 10-20 mcg/mL. Trough levels of 5-10 or >20 mcg/mL occurred in 13 and 11 patients, respectively. A moderately positive correlation between trough and predicted AUC24 was found in all patients (Spearman's rho=0.676, p<0.001). In patients with body weight 1200-2000 g and postnatal age >7 days, the serum creatinine of those with trough levels >20 mcg/mL was significantly higher than those with goal trough levels (0.61 vs. 0.45mg/dL, p=0.01). Among those with trough levels >20 mcg/mL, 5 patients received ibuprofen for patent ductus arteriosus closing prior to vancomycin treatment (45%, 5/11), compared to only 3 patients with trough levels <20 mcg/mL (9%, 3/35) (p=0.013). Only half of the neonates receiving empirical vancomycin regimen achieved goal trough levels of 10-20 mcg/mL. Higher serum creatinine or ibuprofen treatment may increase the risk of overly high trough levels. The vancomycin regimen needs further validation and modification to provide adequate dosing for optimal use in neonates.

Individualized vancomycin dosing in infants: prospective evaluation of an online dose calculator

Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level. This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration. A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC0-24) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity. Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC0-24, respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions.

Population Pharmacokinetics and Dosage Optimization of Vancomycin in Pediatric Patients with Skin and Soft Tissue Infections, Bone, and Joint Infections.

Vancomycin is recommended for the treatment of skin and soft tissue infections (SSTI) and bone and joint infections (BJI). However, a detailed investigation of the pharmacokinetic profile and optimal dosing regimens of vancomycin in pediatric patients with SSTI and BJI is lacking. We successfully developed a new PopPK model of vancomycin in this population by using scavenged blood samples with the typical values for clearance (CL) of 0.14 L/h/kg and volume of distribution (V) of 0.5 L/kg. Body weight was confirmed as the significant covariate on CL and V. The optimal dosing regimens of 75 mg/kg/day and 80 mg/kg/day were recommended for this specific population.

Practical approaches to improve vancomycin-related patient outcomes in pediatrics- an alternative strategy when AUC/MIC is not feasible

BackgroundAnecdotal experience and studies have shown that most pediatric patients fail to reach target therapeutic vancomycin trough levels (VTLs) and required higher total daily doses (TDD). This retrospective study aims to evaluate the frequency of hospitalized children who achieved target VTLs with a vancomycin (VNCO) dosing regimen of 40-60 mg/kg/d q6h and to assess the VNCO-TDD required to attain the target and their effects on clinical outcomes in pediatric patients.MethodsAfter ethical approval, patients of 3 month-12 years were evaluated in this chart review study who received ≥ 3 intravenous-VNCO doses and appropriately drawn blood samples of VTLs between October 2019 to June 2020. Data were retrieved for demographic and clinical characteristics, culture reports, VNCO-regimen, subsequent steady-state VTLs, concomitant nephrotoxic medications, and serum creatinine. Clinical pharmacists made interventions in VNCO therapy and higher VNCO-TDD were used. Safety of higher vs standard daily doses and their clinical impact on duration of therapy, hospital stay, and survival were evaluated.ResultsA total of 89 (39.1%) patients achieved target VTLs (SD-group). The smallest proportion (18.2%) of 2–6 years patients achieved target VTLs and reported the lowest mean value of 10.1 ± 0.2 mg/L which was a significant difference (p < 0.05) from all subgroups. Subtherapeutic VTLs were observed in 139 (60.9%) cases (HD-group), who received higher VNCO-TDD of 72 ± 8.9 mg/kg/d q6h to achieve the targets. Duration of therapy in culture-proven septic patients was significantly (p = 0.025) longer in SD-group [18.4 ± 12.2 days] than HD-group [15.1 ± 8.9 days]. Nephrotoxicity and electrolyte imbalance were comparable in groups. Length of hospital stay was significantly (p = 0.011) longer [median 22 (range 8–55) days] in SD-group compared to HD-group [median 16 (range 8–37) days]. Number of patients survived in HD-group were significantly (p = 0.008) higher than SD-group [129 (92.8%) vs 75 (84.3%)].ConclusionInitial Vancomycin doses of 72 ± 8.9 mg/kg/day q6h are required to achieve therapeutic target in 3 months to 12 years patients. High doses are not associated with higher nephrotoxicity than reported with low doses. In addition, efficient pharmacist intervention for the use of higher VNCO-TDD may improve clinical outcomes in terms of duration of therapy, hospital stay, and survival.

External Validation of a Vancomycin Population Pharmacokinetic Model and Developing a New Dosage Regimen in Neonates.

Vancomycin is the drug of choice in the treatment of MRSA infections. In a published vancomycin population pharmacokinetic study on neonates in Singapore healthcare institutions, it was found that vancomycin clearance was predicted by weight, postmenstrual age, and serum creatinine. The aim of this study was to externally validate the vancomycin population pharmacokinetic model to develop a new dosage regimen in neonates, and to compare this regimen with the existing institutional and NeoFax® dosage regimens. A retrospective chart review of neonates who received vancomycin therapy and therapeutic drug monitoring was conducted. The median prediction error percentage was calculated to assess bias, while the median absolute prediction error percentage and the root mean squared error percentage were calculated to assess precision. The new dosage regimen was developed using Monte Carlo simulation. A total of 20 neonates were included in the external validation dataset. Eighteen of them were premature, with a median gestational age of 27.7 (25.9-31.5) weeks and postmenstrual age of 30.5 (27.3-34.3) weeks at the point of vancomycin initiation. No apparent systematic bias was found in the predictions of the model. The external validation performed in the current study found the model to be generally unbiased. Our new vancomycin dosage regimen was able to achieve target trough concentrations and area under the curve (AUC24) at a greater proportion as compared to existing institutional and NeoFax® dosage regimens. The pharmacokinetic model built in the previous study can be used to conduct reliable population simulations of our Asian neonatal population in Singapore. The new dosage regimen was able to achieve target trough concentrations and AUC24 better than existing institutional and NeoFax® dosage regimens.

A study to explore the appropriateness of dosing regimen of vancomycin in critically ill patients in a tertiary care unit of India.

Vancomycin is used in proven or suspected MRSA and MRE infections. An AUC/MIC ratio of ≥400 is the current accepted critical PK/PD"efficacy" target of vancomycin activity. The present study was conducted to ascertain the appropriateness of practice of current dosage regimen of vancomycin (1 g BD) based on population pharmacokinetic approach. A single-center prospective study with the ICU setting of a tertiary care center was conducted. A total of 15 adult patients with sepsis treated with vancomycin were included over 15 months from May 2019 to July 2020. Blood samples were obtained at 5, 10, and 30 minutes and thereafter at 2 and 6 hours following the completion of the vancomycin infusion. The data obtained from HPLC estimation was analyzed using a population pharmacokinetic approach with NLME, Phoenix 8.3.2.166. The pharmacokinetic model was based on covariates such as bodyweight and urinary creatinine clearance to predict drug concentrations. A total of 83 vancomycin blood samples were analyzed. The mean AUC0-last and AUC0-∞ in patients who improved and died were (AUC(0-last)=293 (152.97); AUC(0-∞)=535.14 (353.67) and (AUC(0-last)=137.19 (51.37); AUC(0-∞)=582.12 (1036.09) respectively, the difference between the two outcome groups was not statistically significant (p=0.104). The pharmacokinetic model was best described by a two-compartment linear model. The goodness-of-fit plots showed that the final covariate pharmacokinetic model (having bodyweight and urinary creatinine clearance) adequately described the observed vancomycin concentrations. Based on the finding of the study it was concluded that 1 g BD dosing of vancomycin is inappropriate. Including covariates such as urinary creatinine clearance and weight in the pharmacokinetic model helped predict drug concentrations more accurately. However, further studies are required to demonstrate efficacy regarding applying this strategy.

Predicted Vancomycin Dosage Requirement in Patients With Hematological Malignancies and Dosage Dynamic Adjustment.

Purpose: The purpose of this study was 1) to predict the requisite vancomycin daily dose (D van ) used in the target patients suffering from both bacterial infection and hematological malignancies and 2) to construct a vancomycin-dose-graphical tool to assist clinicians to develop vancomycin dosing regimens and further 3) to establish a programming process for vancomycin dynamic dosage adjustment to help clinicians to adjust vancomycin dosing regimens according to physiological and pathogenic factors of the target patients. Methods: The D van model associated with microbial susceptibility, vancomycin pharmacokinetics, and dosing parameters was established, and the D van was estimated based on the established D van model and using Monte Carlo simulations. D van achieving 90% of probability of target attainment (PTA) for bacterial isolate or cumulative fractions of response (CFR) for the bacterial population at a ratio of daily area under the curve (AUC24) to the minimum inhibitory concentration (MIC) [i.e., AUC24/MIC] of 400–600 was considered sufficient to treat infection occurring in the target patients. On the basis of the predicted D van , the physiological states of patients, and the pathogenic variables of infection, a vancomycin-dose-graphical tool for the target patients and a programming process for vancomycin dynamic dosage adjustment were constructed. Results: This study predicted the requisite D van used in patients suffering from both bacterial infection and hematological malignancies and constructed a vancomycin-dose-graphical tool for the target patients, at different physiological states and pathogenic variables, to formulate vancomycin dosing regimens. Also, this study established and expounded the formulation process of vancomycin dosage dynamic adjustment according to fluctuant renal function of the target patients. Conclusion: With the tools, the required D van or vancomycin dosing regimens for the target patients, at different physiological states and pathogenic variables, can be readily known, whether or not vancomycin dynamic dosage adjustment is required.

Optimizing Antimicrobial Dosing for Critically Ill Patients with MRSA Infections: A New Paradigm for Improving Efficacy during Continuous Renal Replacement Therapy.

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30–35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6–8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8–10 mg/kg every 24 h was optimal under 30–35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin.

Methods of Therapeutic Drug Monitoring to Guide Vancomycin Dosing Regimens: Trough Concentration versus Ratio of Area Under the Curve to Minimum Inhibitory Concentration.

The most recent vancomycin monitoring guideline recommends targeting a value for area under the curve (AUC) of 400 to 600 mg*h/L, with an assumed minimum inhibitory concentration (MIC) of 1 mg/L. Few studies have investigated the effect of this method on vancomycin dosing regimens, relative to a target trough concentration of 15 to 20 mg/L. To compare vancomycin dosing regimens generated with the 2 monitoring methods. This retrospective chart review included hospitalized patients who received vancomycin between May 2019 and April 2020. The dosing regimens were compared, with the paired Student t test, in terms of unit dose, daily dose, and dosing interval. Variables of interest were collected from electronic medical charts. A pharmacy resident used first-order pharmacokinetic equations to determine dosing regimens based on AUC monitoring. Local pharmacists retrospectively determined dosing regimens for trough-based monitoring. Of 100 courses of treatment initially identified, 66 were included in the analysis. The unit dose was similar with the 2 methods (1086 mg with AUC-based monitoring versus 1100 mg with trough-based monitoring; p = 0.62). AUC monitoring was associated with a 12.8% lower daily dose (2294 mg versus 2630 mg; p < 0.001) and a 13.5% longer dosing interval (13.24 h versus 11.67 h; p < 0.001) relative to trough-based monitoring. AUC monitoring also generated a lower extrapolated trough concentration (12.90 mg/L versus 16.22 mg/L; p < 0.001). A target trough concentration of 15 to 20 mg/L was confirmed as being unnecessarily high. AUC monitoring could allow a reduction in daily vancomycin dose and an extension of the dosing interval relative to trough-based monitoring.

Implementation of a Pharmacist-Driven Vancomycin and Aminoglycoside Dosing Service in a Pediatric Hospital.

Pharmacy-driven antibiotic dosing services have been shown to improve clinical outcomes in adult patients. This study evaluated the effect of a pharmacist-driven antimicrobial dosing service on the percentage of therapeutic serum concentrations achieved following initial vancomycin or aminoglycoside dosing regimens. A secondary objective was to determine the effect of the dosing service on nephrotoxicity in pediatric patients. This single-center, retrospective study used data obtained from an electronic medical record to evaluate the utility of a pharmacist-driven vancomycin or aminoglycoside dosing protocol. Assessments of target, subtherapeutic, and supratherapeutic serum concentrations were evaluated. The occurrence of changes in serum creatinine and presentation of acute kidney injury (AKI) were also determined. The incidence (n [%]) of a therapeutic initial serum concentration was not statistically significant between pre-protocol and post-protocol groups (21 [46.7%] vs 22 [48.9%], respectively; p = 0.834). The incidence of initial supratherapeutic concentrations (19 [42.2%] vs 7 [15.6%]; p = 0.005) and the average number of supratherapeutic concentrations per antibiotic course (0.76 vs 0.26; p = 0.01) were higher in the pre-protocol group compared with the post-protocol group. The incidence of AKI was significantly lower in the post-protocol group (2.2% vs 13.3%; p = 0.049). Implementation of a pharmacist-driven dosing service did not affect the likelihood of achieving an initial therapeutic concentration. However, it did reduce the likelihood of both supratherapeutic concentrations and AKI. Additional studies in pediatric patients are needed to affirm the use of pharmacist dosing services.

A machine learning model that emulates experts’ decision making in vancomycin initial dose planning

Vancomycin is a glycopeptide antibiotic that is a primary treatment for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended.Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician's experience and expertise.In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. Although small training sets were used, we established a predictive model with a target attainment rate comparable to those of experts, another ML model, and commonly used vancomycin dosing software. Our strategy will help develop an expert-like predictive model that aids in decision making for initial vancomycin dosing, particularly in settings where dose planning consultations are unavailable.